Gallbladder Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma With Gallstone Pancreatitis and Prostate Cancer

Primary mucosa-associated lymphoid tissue (MALT) lymphoma of the gallbladder is an extremely rare disease. We describe a case of a 79-year-old man with chronic hepatitis C-related cirrhosis presenting with acute epigastric pain and laboratory findings consistent with gallstone pancreatitis. He underwent a cholecystectomy, and histopathology review of the surgical specimen revealed a primary MALT lymphoma of the gallbladder. Staging studies revealed no evidence of metastatic disease but incidentally identified a malignancy of the prostate. The patient’s gallbladder MALT lymphoma was managed conservatively with surgery and active surveillance, and he remains disease-free at two years status post surgery. This case expands the clinical spectrum of gallbladder MALT lymphoma, with, to our knowledge, the first report of pancreatitis as the presenting symptom. It underscores the importance of considering lymphoid neoplasms in atypical gallbladder disease and highlights the need to further evaluate the potential role of chronic hepatic inflammation in its pathogenesis.

Mucosa-associated lymphoid tissue (MALT) lymphoma of the gallbladder, also known as extranodal marginal zone lymphoma, is a rare type of B-cell lymphoma with fewer than 20 cases reported in the literature to date [1-18] and 15 cases registered in the Surveillance, Epidemiology, and End Results (SEER) database [19]. MALT lymphomas are low-grade B-cell neoplasms arising from acquired lymphoid tissue in non-lymphoid organs. Gallbladder lymphoma accounts for less than 2% of all gallbladder malignancies [20], of which MALT lymphomas make up one of the most common histological subtypes along with diffuse large B-cell lymphoma and follicular lymphoma [13,19,21]. The pathophysiology of gallbladder MALT lymphoma is not fully understood, with several hypotheses, including the roles of chronic inflammation and antigenic stimulation in driving B-cell proliferation [13,22]. We present a case of primary gallbladder MALT lymphoma uniquely presenting as pancreatitis and discuss treatment options and management, as well as the concurrent management of an incidental prostate adenocarcinoma.

A 79-year-old male patient with a history of Child-Pugh class A hepatic cirrhosis secondary to hepatitis C presented to the emergency department (ED) with an acute onset of severe epigastric pain. At the time of presentation, laboratory evaluation revealed elevated lipase, transaminases, and alkaline phosphatase, and a total bilirubin of 2.74 mg/dL (Table 1). He had a significant medical history, including Paget’s disease of the bone, hypertension, hyperlipidemia, chronic normocytic anemia, glaucoma, and a past colonoscopy revealing high-grade dysplasia. His surgical history includes carpal tunnel surgery and back surgery. His family history included prostate cancer, heart disease, and bone cancer. He reported a distant smoking history as well as a history of heavy alcohol use. An abdominal ultrasound was obtained in the ED, which revealed multiple tiny gallstones and sludge in the gall bladder, as well as findings consistent with known liver cirrhosis (Figure 1). An abdominal CT with contrast revealed gastric wall thickening compatible with gastritis, moderate splenomegaly, cholelithiasis, and sclerotic pelvic bones consistent with known Paget’s disease (Figure 2). Given his clinical diagnosis of acute pancreatitis and imaging findings suggesting gallbladder pancreatitis, he subsequently underwent a laparoscopic cholecystectomy. Pathological review of the specimen was consistent with a normal-appearing gallbladder with numerous calculi. The gallbladder measured 7.8 x 4 x 3.5 cm in size, and the mucosa was tan-pink, smooth, and glistening. Examination of the inner lumen revealed numerous dark green friable calculus fragments with tan-pink, glistening, and velvety mucosa. The average wall thickness was 0.2 cm with unremarkable cut surfaces. Histologic examination of the gallbladder revealed a diffuse submucosal lymphoid infiltrate composed predominantly of small to medium-sized lymphocytes with mildly irregular nuclear contours, moderately dispersed chromatin, and inconspicuous nucleoli (Figures 3A-3B). Mitotic figures were rare, and no areas of necrosis, sheets of large, transformed cells, or Hodgkin-like cells were identified. Scattered plasma cells were present. The architectural pattern and cytologic features were inconsistent with a reactive lymphoid process and raised concern for a low-grade B-cell lymphoproliferative disorder. Immunophenotypic studies demonstrated that the lymphoid population was composed of CD20-positive B cells (Figure 3C) and negative for CD3 (Figure 3D), CD5, CD10, CD23, and cyclin D1, thereby excluding entities such as chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, and follicular lymphoma. In situ hybridization showed kappa light chain restriction, confirming clonality. CD23 highlighted a disrupted follicular dendritic cell meshwork, and CD138 demonstrated plasma cells that were polyclonal by kappa and lambda expression. Taken together, the morphologic and immunophenotypic findings support a diagnosis of extranodal marginal zone lymphoma of MALT involving the gallbladder [11,18]. During the operation, no large lymph nodes or liver masses were visualized. He was discharged postoperatively with instructions to follow up with medical oncology for further workup and with gastroenterology for his history of hepatic cirrhosis and colonic dysplasia. At the time of subsequent medical oncology workup, the patient did not present with any B symptoms or palpable lymphadenopathy. A staging study using fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) showed no evidence of FDG-avid malignancy, suggesting lymphomatous involvement. Incidentally, FDG-PET/CT revealed a focal area of FDG uptake in the peripheral zone of the left prostate gland with a maximum standardized uptake value (SUV) of 6.3 (Figure 4). Given the patient’s asymptomatic presentation status post cholecystectomy and lack of disease burden in FDG-PET/CT, the MALT lymphoma was managed with long-term surveillance with medical oncology. Incidental prostate imaging findings were followed by a transperineal biopsy of the prostate, revealing prostatic adenocarcinoma with a Gleason score of 7 (4 + 3). The associated prostate-specific antigen (PSA) at the time of diagnosis was 5.7 ng/mL. (reference range for age 70- 79: 0 to 6.5 ng/mL). He underwent radiation therapy to the prostate using intensity-modulated radiation therapy (IMRT). The prostate received a total of 7000 centigray (cGy) in 28 fractions at 250 cGy per fraction (Figure 5). The patient tolerated radiation therapy well overall, with no significant urinary or gastrointestinal side effects, and continues to be followed with active surveillance via clinical assessment by medical oncology every six months for the first year and subsequently annually. A CT scan of the chest, abdomen, and pelvis performed approximately one year after surgery revealed no evidence of recurrent or metastatic disease. A bone scan obtained approximately two years after surgery was also negative for metastatic disease. Two years after cholecystectomy, he has no clinical evidence of disease. He continues routine follow-up, with no evidence of biochemical recurrence and a down-trending PSA (Table 2).

Gallbladder MALT lymphoma is an infrequent entity with few cases described in the literature (Table 3). Our case broadens the clinical spectrum by identifying gallstone pancreatitis as the primary presenting feature, a phenomenon not previously described in the literature to the best of our knowledge. The pathophysiology of gallbladder MALT lymphoma remains unproven, but it is thought to mirror that of MALT lymphomas of other sites, such as the stomach or liver. However, a unique factor is the lack of organized lymphoid tissue native to the gallbladder. One prevailing hypothesis suggests chronic inflammation, often due to persistent infection or autoimmune processes, leads to the development of acquired lymphoid tissue in the gallbladder [6]. Chronic antigenic stimulation drives B-cell proliferation, which can then undergo malignant transformation [13,22]. This is supported by the common findings of cholelithiasis and chronic cholecystitis, as well as by diagnoses of gallbladder MALT lymphoma [13] and by bile culture studies revealing gram-negative bacterial infections in affected patients [6]. Antigenic stimulation is also hypothesized to induce API2-MALT1 fusion protein synthesis (API2-MALT1 fusion is detected most frequently in MALT lymphomas) as a proposed mechanism of oncogenesis [23], and API2-MALT1 fusion has been observed in one case of gallbladder disease [11]. Another hypothesis by Angelopoulou et al. suggests that malignant lymphoid tissue may originate and migrate from outside the gallbladder [24], a hypothesis supported by a prior report of a MALT lymphoma diagnosed in the stomach, small intestine, and gallbladder over several years, with molecular clonality across tumor samples [25]. These mechanisms underscore the significance of our patient’s history of chronic hepatitis C and liver cirrhosis. While hepatitis C and cirrhosis are established risk factors for MALT lymphoma of the liver [26,27], their potential role in gallbladder MALT lymphoma pathogenesis remains unstudied and merits further investigation. Autoimmune diseases that are also known risk factors for MALT lymphomas in other sites, such as Sjogren’s syndrome and Hashimoto’s thyroiditis, may contribute to gallbladder disease. However, direct evidence is limited [13,22]. Gallbladder MALT lymphoma occurs predominantly in older patients compared to other subtypes [19], with mean reported ages of approximately 76 and 47 years, respectively [13], and a slight female predominance [18]. In this demographic, concurrent malignancies and chronic comorbidities are common, as with our case, where the concurrent incidental finding of prostate cancer occurred at the time of gallbladder MALT lymphoma evaluation. These findings emphasize the importance of comprehensive oncologic assessment and individualized management strategies. A 2017 review by Honda et al. reported 17 cases of primary MALT lymphoma of the gallbladder [1-13,15,16,18]. The most common presenting signs of MALT lymphoma are those of local gallbladder pathology, such as right upper quadrant abdominal pain, jaundice, and nausea. Cholecystolithiasis was found in two-thirds of cases in a prior review [18] and was notably common, even compared with other subtypes. In a report of 19 cases of gallbladder lymphoma, 60% of those with the MALT subtype had gallstones, versus 12.5% in other subtypes [13]. Cases of gallbladder MALT lymphoma are typically incidentally diagnosed via postoperative immunohistologic staining, following gallbladder resection with concern for gallbladder carcinoma or cholecystitis. There are no known reports of preoperative diagnosis of MALT lymphoma of the gallbladder to date [18]. Nearly all cases in the literature present with regional disease; one reported case in a population analysis of the SEER database involved distant disease [19]. Imaging modalities such as ultrasound and CT are often unable to distinguish gallbladder MALT lymphoma from more common entities, including adenocarcinoma and cholecystitis, because most cases present with nonspecific clinical findings. The most common imaging findings in the literature included gallbladder wall thickening, polypoid lesions, and gallbladder masses [18]. None of these imaging findings, other than cholelithiasis, were noted in our patient, underscoring the critical role of histopathological evaluation for definitive diagnosis. While there is no reliable way to diagnose gallbladder MALT lymphoma preoperatively, the most frequent findings among the limited case literature, which include a combination of homogeneous submucosal wall thickening and a mild clinical course on presentation, should prompt consideration of lymphoma in the differential. In prior cases, MALT lymphomas were diagnosed only after pathologic examination of the resected specimen [18], and cholecystectomy remains the cornerstone for definitive diagnosis and is also therapeutic for localized disease. There is no established consensus on the management of gallbladder MALT lymphoma due to its rarity. However, surgical resection via cholecystectomy, which often occurs before diagnosis, has been the mainstay of therapy in reported cases [18]. Prior reports show excellent local control and prognosis. There is only one reported case of MALT lymphoma of the gallbladder followed by cholecystectomy resulting in gastric recurrence five years later, which was treated with adjuvant chemotherapy and resulted in complete remission [7,18]. There have been no reported deaths from gallbladder MALT lymphoma in the literature to the best of our knowledge [14,17,18]. Past cases have reported rapid mass growth with local hepatic bed invasion, suggesting that resection may be preferred over watchful waiting, which is used to manage other types of low-grade B-cell lymphomas, such as follicular lymphoma [18]. In our case, our patient remains free of recurrence at over two years after cholecystectomy and initial diagnosis of the gallbladder MALT lymphoma.

Gallbladder MALT lymphoma is a rare entity, most often diagnosed incidentally after cholecystectomy. This case, to our knowledge, is the first reported instance of MALT lymphoma of the gallbladder presenting with pancreatitis as the primary symptom. In older adults, the primary demographic for gallbladder MALT lymphoma, comprehensive assessment and management of comorbidities such as concurrent malignancies observed in our patient are essential to optimize outcomes. Primary treatment for this disease is surgery with chemotherapy for recurrent disease. This case report highlights the importance of considering lymphoid neoplasms in the differential diagnosis of gallbladder disease, even when the clinical picture initially suggests a benign inflammatory or obstructive process.